Purpura Fulminans

Etiology

Purpura fulminans is a rapidly evolving syndrome of skin microvascular thrombosis and hemorrhagic necrosis. It is considered a sign of certain systemic diseases rather than a disease unto itself. The 3 types of purpura fulminans are neonatal, idiopathic, and acute infectious.  Neonatal purpura fulminans is associated with a hereditary deficiency of the anticoagulants protein C,  protein S, and antithrombin III. It manifests very early in life and treatment is aimed at these deficiencies. [1] Idiopathic purpura fulminans is thought to be a post-infectious autoimmune disorder often following an initiating febrile illness, which later leads to rapidly progressive purpura. In this form, a relative deficiency of protein S is believed to be causative. Acute infectious purpura fulminans is the third and most common type. It manifests as a skin finding in the most severe septic patients as well as in necrotizing fasciitis with a predilection to certain infectious agents.

Epidemiology

First described in 1884, purpura fulminans remains a relatively rare disease, and thus, most of the articles written about it are case reports and case series. Each form of purpura fulminans has a different prevalence. The hereditary neonatal form with severe protein C deficiency occurs in about 1:1,000,000 live births. [2]Acute infectious purpura fulminans can be seen in up to 10% to 20% of patients who develop meningococcal septicemia. Meningococcus and Streptococcus pneumoniae were identified as the most common bacterial triggers, and varicella was the most common viral trigger. Acute infectious purpura fulminans has been found to be more common in patients who are physically or functionally asplenic. The idiopathic post-infectious form is very rare with only a few hundred cases reported.

Pathophysiology

Purpura fulminans is the acute onset of often rapidly progressing cutaneous hemorrhage and necrosis caused by dermal vascular thrombosis and disseminated intravascular necrosis.  It occurs in 3 clinical settings:

1. Neonatal purpura fulminans is a manifestation of inherited protein C or, less commonly, protein S deficiency. [3]
2. Idiopathic or acquired purpura fulminans occurs approximately 7 to 10 days after an infectious disease, usually involving the skin (usually varicella or scarlet fever). [4][5]
3. Acute infectious purpura fulminans occurs during an acute illness, usually sepsis with endotoxin producing gram-negative bacteria. [6]

All types of purpura fulminans involve dysfunction of hemostasis with a shift to a disease state with overwhelming procoagulation.

Neonatal purpura fulminans is associated with a hereditary deficiency of the anticoagulants protein C and S. These proteins are vitamin-K dependent cofactors which are pro-fibrinolytic. Protein C is one of the major inhibitors of the coagulation system which when activated inhibits factor Va and VIIIa which in turn down-regulate thrombin synthesis. Neonates typically present with massive venous and arterial thrombosis of the skin and other organs within 5 days of birth.

Acute infectious purpura fulminans is the most common type and is associated with an acquired deficiency of protein C. The mechanism involves a disruption of the coagulation balance. Bacterial endotoxin triggers consumption of proteins C and S and antithrombin III. This pro-coagulative state leads to thromboses of dermal vessels and is associated with disseminated intravascular coagulation. The skin lesions may present early as petechial rashes. These rapidly progress to larger ecchymotic areas. Later in the course, hemorrhagic bullae may form which contribute to the classic hard eschars characteristic of purpura fulminans.

Idiopathic purpura fulminans, the rarest form of the disease, has been associated with the development of anti-protein S antibodies. These antibodies bind to protein S and get excreted. This causes to a transient protein S deficiency which leads to hypo-activation of the protein C pathway and a hypercoagulable state similar to what was described above.

History and Physical

The skin findings of purpura fulminans have a characteristic appearance and evolution. Purpura fulminans begins with erythema, which develops irregular central areas of blue-black hemorrhagic necrosis. In some cases, vesicles and bulla form. The affected skin initially is painful and indurated, but in the later stages, there may be a total loss of sensation. Secondary infection of gangrenous tissue may occur. Necrosis may extend to deeper tissues.

In general, the history and physical exam for purpura fulminans should be aimed at early recognition and determination of the underlying cause. Make sure to thoroughly examine the patient’s skin, especially in patients who could be presenting with necrotizing fasciitis. Early in the diagnosis of associated diseases, the skin findings may be subtle, so it is important to keep this diagnosis in your differential. Petechial rash or bruising in a neonate or septic patient should trigger consideration of purpura fulminans. Components of a patient’s history include a history of severe infections or trauma as well previous splenectomy. Because of the association with DIC patients may experience bleeding from multiple sites including mucous membranes, areas of trauma or the rectum. Because of the association with severe septic shock, the patient may experience symptoms of end-organ damage such as hematuria, oliguria, and respiratory distress. Pain out of proportion to exam should always make one consider necrotizing fasciitis.

Evaluation

As noted above, this disease represents an imbalance in the coagulation system. Specific levels of antithrombin III, free protein C, and free and total protein S may help confirm the diagnosis especially in the neonatal form of the disease. Otherwise, the evaluation of patients with purpura fulminans mimics the evaluation of the underlying cause. Searching for inciting infection with labs, cultures, and imaging should follow sepsis guidelines. If the clinician is considering necrotizing fasciitis, white blood cell (WBC) count and a sodium level with or without the other components of the LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score may help the surgeon decide on an early intervention.  Because of the strong association with disseminated intravascular coagulation, one should also evaluate for thrombocytopenia, elevated coagulation factors (PT, PTT), increased d-dimer assay (or serum fibrin degradation products), and a decreasing fibrinogen level.

Treatment / Management

The treatment of all types of purpura fulminans starts with supportive care and adequate hydration. This is important because of the widespread thrombosis associated with this disease can lead to damage of multiple end organs. As this commences, finding and treating the underlying cause is essential. Anticoagulation may be stared to prevent further necrosis. There may need for replacement of blood, factors, and platelets lost because of both the pro-coagulable state and DIC. Finally, early surgical debridement for areas which have become necrotic has been shown to decrease mortality.

In the neonatal form of the disease hydration, platelet transfusion, followed by an assessment of protein C and S levels followed closely with fresh frozen plasma transfusions are the mainstay of treatment. Heparin and warfarin have been used as anticoagulants, and later protein C concentrate can be added if this deficiency is found. [7]

The treatment of idiopathic purpura fulminans is similar to what is described above. Additionally, there may be a role for immunomodulation with corticosteroids.

In the acute infectious form, broad-spectrum antibiotics should include coverage of Neisseria meningitidis, Streptococcus, Staphylococcus, and Clostridia species. Often carbapenem or vancomycin with beta lactam-beta lactamase inhibitor combinations are used. Clindamycin is often included as it has specific properties which inhibit some of the toxins which allow this disease to progress. IVIg therapy is also used because of antibodies to these toxins. Activated protein C may be administered to reduce the inflammatory cascade, restore the coagulation balance which may decrease the progression of purpuric skin injury. In acute infectious purpura fulminans, the decision to anticoagulated is based on the occurrence of concurrent DIC.[8][9]

In all forms of the disease repeated tissue assessments with debridement of affected areas are carried out as needed. Repeated surgeries are often required.

Differential Diagnosis

• Calciphylaxis

• Coumadin necrosis

• Meningococcemia

• Necrotizing fascitis

• Thrombotic thrombocytopenic purpura

• Toxic shock syndrome 

• thrombophlebitis

• Vasculitis